Caffeine and stress have some cardiovascular (CV) and neuroendocrine (NE) effects in common which suggests that caffeine could augment or intensify CV and NE responses to stress which may have pathological effects leading to CV disease. The long-term objectives of this research program are the investigation of potential caffeine-stress interactions for CV and NE responses. We have shown that caffeine can add to or magnify CV responses to stress. We propose to address three new questions concerning caffeine-stress interactions: Can caffeine also intensify NE responses to stress? Do patterns of habitual caffeine use influence the magnitude of caffeine's CV and NE effects (Does tolerance develop)? and Does nicotine interact with caffeine and stress to produce even greater CV and NE responses with implications for pathology. The first of three studies will examine the effects of caffeine on both CV and NE (catecholamine and cortisol) responses to psychological stress in the lboratory. Heart rate, blood pressure, and skeletal muscle vasomotor activity will be measured and samples of blood drawn under conditions of rest and experimental stress in two sessions in which caffeine or placebo is administered. The second study will assess the effects of caffeine on CV and NE activity in the same subjects during the activities of the normal day. Ambulatory measures of heart rate and blood pressure and measures of urinary excretion of catecholamines and cortisol will be obtained from subjects on days in which caffeine or placebo are administered. In both studies, we will examine whether the magnitude of caffeine effects is related to habitual patterns of caffeine use assessed by a 1-week intake diary. In the third study, the effects of nicotine, caffeine and their combination will be assessed in a four session, placebo controlled design in which CV and NE activity at rest and during stress are measured as in Study 1. These studies will help us understand the mechanisms of caffeine's effects on stress, will determine whether tolerance to these effects appears with regular caffeine use, and whether nicotine and caffeine, so commonly used together in society, combine to further intensify CV and NE responses to stress. This knowledge will help to clarify the role which caffeine consumption may have in the pathogenesis of cardiovascular disease.